Sustained release compositions of drugs

ABSTRACT

A sustained release pharmaceutical composition has been developed. The composition resists dose dumping when broken, crushed or chewed, which enhances the safety of the dosage form should it be accidentally or intentionally physically compromised. In the preferred embodiment, a drug is modified to increase its lipophilicity. In preferred embodiments the modified drug is homogeneously dispersed within microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments the drug containing microparticles coated with one or more coating layers. The sustained release composition retards the release of drug, even if the physical integrity of the formulation is compromised (for example, by chewing or crushing) and the resulting material is placed in 0.1N HCl. However, when administered as directed, the drug is slowly released from the composition as the composition is broken down or dissolved gradually within the GI tract by a combination of diffusion, surfactant action of bile acids, mechanical erosion, and in some embodiments, enzymatic degradation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part of U.S. Ser. No. 10/614,866filed on Jul. 7, 2003 entitled “Abuse-Deterrent PharmaceuticalCompositions of Opiods and Other Drugs”, which claims priority to U.S.Ser. No. 60/393,876 filed Jul. 5, 2002 entitled “Abuse-ResistantFormulations of Oxycontin and Other Drugs” by Alexander M. Klibanov,Stephen L. Buchwald, Timothy M. Swager, and Whe-Yong Lo; U.S. Ser. No.60/436,523 filed Dec. 23, 2002 by Alison B. Fleming, Roman V. Rariy,Alexander M. Klibanov, Whe-Yong Lo, and Jane Hirsh; U.S. Ser. No.60/443,226 filed Jan. 28, 2003 by Jane Hirsh, Alison B. Fleming,Alexander M. Klibanov, and Whe-Yong Lo; U.S. Ser. No. 60/463,514 filedApr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming, Roman V. Rariy,Stephen L. Buchwald, and Timothy M. Swager; and U.S. Ser. No. 60/463,518filed Apr. 15, 2003 by Jane C. Hirsh, Alison B. Fleming and Roman V.Rariy. The disclosures in the applications listed above are hereinincorporated by reference.

BACKGROUND OF THE INVENTION

The present invention is generally in the field of pharmaceuticalcompositions, and specifically relates to compositions that are designedto provide a sustained release of drug over time after oraladministration.

Sustained release pharmaceutical formulations, which release drug overan extended period of time, are widely used in the pharmaceuticalindustry. Such formulations provide several potential advantages to thepatient including: (1) the convenience of reduced dosing frequency, (2)optimization of therapy by providing a smoother, more constant, plasmalevel of drug, and (3) a potential reduction in side effects.

Several formulations that achieve sustained release of drug whenadministered orally have been described in the literature. In general,oral sustained release dosage forms can be classified asdiffusion-controlled, erosion-controlled or osmotic pressure-controlled.For diffusion based systems, control of drug release is usually achievedby dispersing the drug in an inert insoluble matrix or by coating a drugcontaining core with an insoluble polymeric film. Erosion controlledformulations can be achieved by dispersing the drug in a slowly solublecarrier material or by coating the drug with a slowly soluble material.Osmotic systems are monolithic in nature and consist of a corecontaining an osmotically active drug or a drug in combination with anosmotically active salt, surrounded by a semi-permeable membranecontaining a small orifice.

Although many types of sustained release dosage forms have beendescribed, currently available sustained release dosage forms have someinherent disadvantages. Monolithic dosage forms, such as tablets orcapsules, can be difficult for some patients to swallow. Since sustainedrelease formulations can be subject to dose dumping when they arecrushed, these products come with specific instructions not to break,chew or crush them. While there are some available multiparticulateformulations (such as particles-in-capsule and sachet) that can beadministered as particles, for example after sprinkling in applesauce,such formulations are still potentially dangerous if the particles areaccidentally chewed, broken or their physical integrity is compromised,thus resulting in the destruction of the sustained release feature.

It is therefore an object of the present invention to provide asustained-release, multiparticulate pharmaceutical composition thatresists dose dumping when accidentally broken, crushed or chewed.

SUMMARY OF THE INVENTION

Sustained release pharmaceutical compositions and the methods of makingand using the composition have been developed. The compositions can beused to improve the convenience and safety of administration when asustained release dosage form is desired. In the preferred embodiment,the drug is chemically modified to increase its lipophilicity. In otherembodiments, the formulation contains lipophilic or water-insolublematerials or is made using a process which increases the lipophilicityand/or water-insolubility of the composition. In some embodiments, theindividual drug-containing microparticles or drug particles are coatedwith one or more independent coating layers.

The compositions retard the release of drug, even if the physicalintegrity of the dosage form is compromised (for example, by breaking orchewing).

The pharmaceutical compositions, when administered orally, result in adesired drug release profile. Such a release profile provides atherapeutic effect for an extended period of time, typically from 6 to24 hours. Additional compositions are provided which achieve a smallimmediate dose that precedes the sustained release of drug. Thecompositions disclosed herein may optionally include a combination ofactive pharmaceutical agents.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are sustained-release pharmaceutical compositions andthe method of making and using the compositions.

I. Compositions

As used herein, “composition” or “compositions” refers to the drugdosage unit for administration to a patient. This may also be used inreference to the final dosage form (tablet or capsule) or to componentsof the final dosage form (microparticles or coated microparticles).

Currently available sustained release formulations are subject to dosedumping when chewed or crushed because mechanical destruction of thedosage form exposes the encapsulated drug and allows for immediatedissolution of the drug into aqueous media. Two properties of the dosageform that contribute to this outcome are (1) the ease with which drug isexposed when the compositions are broken or chewed and (2) the highwater solubility of the drug salt form.

In the composition disclosed herein, one or both of these properties arealtered in order to achieve a composition which resists dose dumpingwhen chewed or broken. Specifically, in the preferred embodiment, thedrug is modified to increase its lipophilicity and, in additionalpreferred embodiments, is then homogeneously dispersed within a materialthat is either slowly soluble or not soluble in water and subsequentlyformulated into microparticles. The drug may be present in the form ofdiscrete particles or may be partially or fully dispersed in the carriermaterial on a molecular level.

The sustained release composition preferably includes a drug modified toincrease its lipophilicity. In other preferred embodiments, the drug ishomogenously dispersed within microparticles composed of a material thatis either slowly soluble in water or water insoluble. The compositionsslow the release of drug if the dosage form is broken or chewed and theresulting material is swallowed since most of the drug will remainassociated with or entrapped within portions of the core material of themicroparticles. In some embodiments the drug containing microparticlesor individual drug particles are coated with one or more coating layers.

A. Drugs to be Formulated

There are many drugs that it is desirable to deliver using thecompositions described herein.

Exemplary drug agents useful for forming the composition describedherein include, but are not limited to, analeptic agents; analgesicagents; anesthetic agents; antiasthmatic agents; antiarthritic agents;anticancer agents; anticholinergic agents; anticonvulsant agents;antidepressant agents; antidiabetic agents; antidiarrheal agents;antiemetic agents; antihelminthic agents; antihistamines;antihyperlipidemic agents; antihypertensive agents; anti-infectiveagents; antiinflammatory agents; antimigraine agents; antineoplasticagents; antiparkinsonism drugs; antipruritic agents; antipsychoticagents; antipyretic agents; antispasmodic agents; antitubercular agents;antiulcer agents; antiviral agents; anxiolytic agents; appetitesuppressants; attention deficit disorder and attention deficithyperactivity disorder drugs; cardiovascular agents including calciumchannel blockers, antianginal agents, central nervous system (“CNS”)agents, beta-blockers and antiarrhythmic agents; central nervous systemstimulants; diuretics; genetic materials; hormonolytics; hypnotics;hypoglycemic agents; immunosuppressive agents; muscle relaxants;narcotic antagonists; nicotine; nutritional agents; parasympatholytics;peptide drugs; psychostimulants; sedatives; steroids; smoking cessationagents; sympathomimetics; tranquilizers; vasodilators; beta-agonist; andtocolytic agents.

Drugs that are most preferable include those that are currentlyformulated as sustained or controlled release compositions, where drugrelease is intended to occur over a prolonged period of time through thegastrointestinal tract, and immediate or burst release is undesirable.Specific examples of agents currently formulated in sustained orcontrolled release formulations include, but are not limited to,acetaminophen, acetazolamide, albuterol, alfuzosin, alprazolam,amoxicillin, amphetamine, aspirin, brompheniramine, bupropion,carbamazepine, carbidopa, carbinoxamine, cetirizine, chlorpheniramine,ciprofoxacin, clarithromycin, clavulanate, clorazepate, colestipol,desloratidine, dexbrompheniramine, dexmethylphenidate,dextroamphetamine, dextromethorphan, diclofenac, diethylpropion,diltiazem, dipyridamole, disopyramide, divalproex sodium, doxazosin,doxycycline, enalapril, etodolac, felodipine, fexofenadine, fluoxetine,fluvastatin, glipizide, guaifenesin, hyoscyamine, indomethacin,isosorbide dinitrate, isosorbide mononitrate, isradipine, ketoprofen,levodopa, loratidine, lovastatin, mesalamine, metformin,methscopolamine, methylphenidate, metoprolol, metronidazole,minocycline, morphine, naproxen, niacin, nicardipene, nifedipine,nsoldipine, nitroglycerin, orphenadrine, oxybutynin, oxycodone,oxymorphone, papaverine, paroxetine, pentoxifyline, phendimetrazine,phenylephrine, phenyloin, procainamide, propranolol, pseudophedrine,pyridostigime, quinidine, ranolazine, tamsulosin, theophylline,tolterodine, tramadol, trandolapril, venlafaxine, verapamil, andzolpidem.

The terms “drug”, “active agent”, and “pharmacologically active agent”are used interchangeably herein to refer to a chemical compound thatinduces a desired pharmacological and/or physiological effect. The termsalso encompass pharmaceutically acceptable derivatives of those activeagents specifically mentioned herein, including, but not limited to,salts, solvates, hydrates, complexes with one or more molecules,prodrugs, active metabolites, analogs, and the like. When the terms“active agent”, “pharmacologically active agent” and “drug” are used, orwhen a particular drug, such as oxycodone, is identified, it is to beunderstood as including the active agent per se as well aspharmaceutically acceptable salts, solvates, hydrates, complexes withone or more molecules, prodrugs, active metabolites, and analogs.

Certain compounds described herein may exist in particular geometric orstereoisomeric forms. The composition disclosed herein contemplates allsuch compounds, including cis- and trans-isomers, R- and S-enantiomers,diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof,compounds of different spacial conformations, and other mixturesthereof, as falling within the scope of the invention. Additionalasymmetric carbon atoms may be present in a substituent such as an alkylgroup. All such isomers, as well as mixtures thereof, are intended to beincluded in this invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids.

The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Optionally, the salt can also be formed as part of themanufacturing process for the composition. For fatty acid salts such asoleate, myristate, palmitate or stearate, this can be accomplished bymelting the fatty acid, optionally along with other waxes, and addingthe free base of the drug directly into this melt. Lists of suitablesalts are found in Remington's Pharmaceutical Sciences, 20th ed.,Lippincott Williams & Wilkins, Baltimore, Md., 2000, p. 704, thedisclosure of which is hereby incorporated by reference.

Optionally, the composition described herein can include a combinationof active pharmaceutical agents.

B. Drug Solubility Modification

In preferred embodiments, the solubility characteristics of a drug arealtered prior to incorporation into the formulation. Modification of thedrug to produce a more lipophilic derivative serves to reduce the watersolubility of the drug and thus reduces the aqueous extractability.Furthermore, if the drug is made more lipophilic, it can be solubilizedin the molten carrier material, rather than physically dispersed in aparticulate form. When drug is solubilized in the carrier material it isdifficult to extract drug from the resulting intimately dispersedcomposition.

The terms “lipophilic derivative” and “lipophililic drug derivative”, asused herein, refer to derivatives of the drug that are less soluble inwater than the most soluble salt of the drug. The most soluble salt isselected from either drug alkaline metal salts (for acidic drugs) orsalts of the drug with inorganic acids (for basic drugs). The examplesof the latter include, but are not limited to, hydrohalates, sulfates,and nitrates.

Some of the methods that can be used to alter the drug's lipophilicityare outlined below. It is understood that two or more approaches can becombined to achieve a desired solubility profile.

Methods for Increasing Lipophilicity

In one embodiment drug is made more lipophilic by eliminating orreducing the overall charge of the drug molecule. For example, for abasic drug, a water soluble salt (such as hydrochloride, sulfate, ormaleate) can be converted to a free base using techniques known in theart. Correspondingly, in the case of an acidic drug, a water solublesalt (such sodium, potassium, or the like) can be converted to a freeacid.

In another embodiment, the drug's lipophilicity is increased by forminga salt between a drug molecule and a charged compound. In this case thelipophilicity, or water solubility, of the resulting salt can bemanipulated by varying the counter-ion. In general, lipophilic acids oramines with chain lengths between C₅-C₃₀ are lipophilic counter-ioncandidates. Some specific examples include, but are not limited to,linoleic acid, octanoic acid, lauric acid, stearic acid, palmitic acid,lauryl sulfate, oleic acid, octyl amine, lauryl amine, stearyl amine,palmityl amine, linoleyl amine, and oleyl amine. Other salts which mayincrease lipophilicity and, hence, lipid solubility relative to theparent drug compound include, but are not limited to, pectinate,tannate, phytate, salicylate, saccharinate, acesulfamate, gallate, andterephthalate salts. The counter-ion used for salt formation may also bepolymeric in nature. For example, anionic copolymers based onmethacrylic acid and methyl methacrylate sold under the trade nameEudragit (e.g., Eudragit L 100 and Eudragit S 100), acrylic acidpolymers, and crosslinked acrylic acid polymers may be used to form asalt with drug molecules. Naturally occurring polymers and theirderivatives, for example, carboxymethylcellulose, may also be used toform a salt with the drug molecules. In the case of polymericcounter-ions, the number of drug molecules reacted with the polymer toform a salt may or may not be equimolar with respect to the number ofsalt-forming sites on the polymer chain.

The formation of a salt composed of a pharmaceutically active agent anda fatty acid or amine can be accomplished by a melt process, with orwithout the use of a solvent. One or more fatty acids or amines areheated above their melting point and the pharmaceutically active agent,in free base or acid form, is added to the molten fatty acid or amine,respectively, either directly or after dissolution of the active agentin an appropriate solvent. The fatty acid or fatty amine may be presentin an equimolar amount or may be present in excess with respect to thefree base or free acid of the active agent.

In another embodiment, a drug is covalently modified to increase itslipophilicity. For example, a lipophilic compound can be covalentlyattached to a drug molecule via an ester or amide linkage. Such drugderivatives are cleaved in vivo, thus releasing the parent compound.

C. Drug Containing Microparticles

In preferred embodiments, drugs are formulated with a carrier materialto form microparticles. As used herein, the term “microparticle” refersto a composition including a drug dispersed within a carrier materialand “coated microparticle” refers to a composition including a drugcontaining microparticle or a drug particle coated with one or morecoating layers of material. Microparticles and coated microparticleshave a size range of 10 to 3000 microns in diameter.

Within microparticles, drug is preferably homogeneously dispersed in theform of fine particles within the carrier material. More preferably,drug is partially solubilized in molten carrier material or partiallydissolved with the carrier material in a mutual solvent during theformulation of the microparticles. Most preferably, drug is completelysolubilized in the molten carrier material or completely dissolved withthe carrier material in a co-solvent during the formulation of themicroparticles. This is accomplished through the selection of materialsand the manner in which they are processed.

Carrier materials appropriate for the fabrication of drug containingmicroparticles are either slowly soluble in water or insoluble in water,but capable of degrading within the GI tract by means includingenzymatic degradation, surfactant action of bile acids and mechanicalerosion. As used herein, the term “slowly soluble in water” refers tomaterials that are not dissolved in water within a period of 30 minutes.Preferred examples include fats, fatty substances, waxes, wax-likesubstances and mixtures thereof. Suitable fats and fatty substancesinclude fatty alcohols (such as lauryl, myristyl stearyl, cetyl orcetostearyl alcohol), fatty acids and derivatives, including but notlimited to fatty acid esters, fatty acid glycerides (mono-, di- andtri-glycerides), and hydrogenated fats. Specific examples include, butare not limited to hydrogenated vegetable oil, hydrogenated cottonseedoil, hydrogenated castor oil, hydrogenated oils available under thetrade name Sterotex®, stearic acid, cocoa butter, glyceryl behenate(available under the trade name COMPRITOL 888®), glyceryldipalmitostearate (available under the trade name PRECIROL®), andstearyl alcohol. Mixtures of mono-, di- and tri-glycerides and mono- anddi-fatty acid esters of polyethylene glycol, available under the tradename GELUCIRE®) are also suitable fatty materials. Suitable waxes andwax-like materials include natural or synthetic waxes, hydrocarbons, andnormal waxes. Specific examples of waxes include beeswax, glycowax,castor wax, carnauba wax, paraffins and candelilla wax. As used herein,a wax-like material is defined as any material which is normally solidat room temperature and has a melting point of from about 30 to 300° C.

In some cases, it may be desirable to alter the rate of waterpenetration into the hydrophobic drug containing microparticles. To thisend, rate-controlling (wicking) agents may be formulated along with thefats or waxes listed above. Examples of rate-controlling materialsinclude certain starch derivatives (e.g., waxy maltodextrin and drumdried corn starch), cellulose derivatives (e.g.,hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose,and carboxymethylcellulose), alginic acid, lactose and talc.Additionally, a pharmaceutically acceptable surfactant (for example,lecithin) may be added to facilitate the degradation of suchmicroparticles.

Proteins which are water insoluble, such as zein, are preferred carriermaterials for the formation of drug containing microparticles.Additionally, proteins, polysaccharides and combinations thereof whichare water soluble can be formulated with drug into microparticles andsubsequently cross-linked to form an insoluble network.

Certain polymers may also be used as carrier materials in theformulation of drug containing microparticles. Suitable polymers includeethylcellulose and other natural or synthetic cellulose derivatives.Polymers which are slowly soluble and form a gel in an aqueousenvironment, such as hydroxypropyl methylcellulose or polyethylene oxidemay also be suitable as carrier materials for drug containingmicroparticles.

Encapsulation or incorporation of drug into carrier materials to producedrug containing microparticles can be achieved through knownpharmaceutical formulation techniques. To create a composition thatprotects drug from exposure upon mechanical disruption (e.g., breakingor chewing), the drug is intimately dispersed within the carriermaterial. In the case of formulation in fats, waxes or wax-likematerials, the carrier material is heated above its melting temperatureand the drug is added to form a mixture including drug particlessuspended in the carrier material, drug dissolved in the carriermaterial, or a mixture thereof. Microparticles can be subsequentlyformulated through several methods including, but not limited to, theprocesses of congealing, extrusion, spray chilling or aqueousdispersion. In a preferred process, wax is heated above its meltingtemperature, drug is added, and the molten wax-drug mixture is congealedto form solid, spherical particles via a spraying or spinning diskprocess. Alternatively, the molten wax-drug mixture can be extruded andspheronized to form pellets or beads. Detailed descriptions of theseprocesses can be found in “Remington—The science and practice ofpharmacy”, 20^(th) Edition, Jennaro et. Al., (Phila, Lippencott,Williams, and Wilkens, 2000. Detailed descriptions of the spinning diskprocess can be found in U.S. Pat. Nos. 3,015,128 and 7,261,529.

For some carrier materials it may be desirable to use a solventevaporation technique to produce drug containing microparticles. In thiscase drug and carrier material are co-dissolved in a mutual solvent andmicroparticles can subsequently be produced by several techniquesincluding, but not limited to, forming an emulsion in water or otherappropriate media, spray drying, using a spinning disk process or byevaporating off the solvent from the bulk solution and milling theresulting material.

In addition to modification of the drug itself, processing conditionscan be used to influence the dispersion of the drug withinwater-insoluble or slowly water-soluble material. For example, in thecase where the water in-soluble or slowly soluble material is melted anddrug is fully or partially dissolved under stirring conditions, thetemperature, agitation rate and time of processing will influence thedegree of dissolution achieved. More specifically, a more homogenousdispersion may be achieved with a higher temperature, faster stirringrate and longer processing time. Ultrasound can also be applied to themolten mixture to increase the degree of dispersion and/or the rate ofdissolution of the drug.

In some embodiments, drug in a particulate form is homogeneouslydispersed in a water-insoluble or slowly water soluble material. Tominimize the size of the drug particles within the composition, the drugpowder itself may be milled to generate fine particles prior toformulation. The process of jet milling, known in the pharmaceuticalart, can be used for this purpose. In some embodiments drug in aparticulate form is homogeneously dispersed in a wax or wax likesubstance by heating the wax or wax like substance above its meltingpoint and adding the drug particles while stirring the mixture. In thiscase a pharmaceutically acceptable surfactant may be added to themixture to facilitate the dispersion of the drug particles.

For formulations including a pharmaceutically active agent in the freebase form and one or more fatty acids, a homogeneous molten mixture, inwhich the drug particles are completely dissolved, can be achieved inthe following manner. The one or more fatty acid(s) are heated abovetheir melting point but below the melting point of the active agent. Theactive agent in free base form is mixed with the molten fatty acid untila clear, homogeneous mixture is formed. The active agent may be added inthe solid form or may first be dissolved in an appropriate solvent.Optionally, one or more fats, fatty substances, waxes, and/or wax-likesubstances are co-melted into the mixture, either before the addition ofthe active agent or following the addition of the active agent. It isbelieved that a clear solution is formed due to the formation of a saltbetween the free base of the active agent and the one or more fattyacids present in the formulation. An analogous composition may be formedusing the free acid of the active agent, one or more fatty amines, and,optionally, one or more fats, fatty substances, waxes, and/or wax-likesubstances.

D. Coated Drug Containing Microparticles

In some embodiments, drug containing microparticles or drug particlesare encapsulated. Drug containing microparticles can be encapsulated inwater insoluble materials, slowly water soluble materials, or materialswith pH dependent solubilities.

In general, any coating procedure which provides a contiguous coating oneach microparticle without significant agglomeration of particles may beused. Coating procedures known in the pharmaceutical art including, butnot limited to, fluid bed coating processes and microencapsulation maybe used to obtain appropriate coatings. Detailed descriptions of theseprocesses can be found in “Remington—The science and practice ofpharmacy”, 20^(th) Edition, Jennaro et. Al., (Phila, Lippencott,Williams, and Wilkens, 2000.

The water-insoluble coating materials may be any of a large number ofnatural or synthetic film-formers used singly, in admixture with eachother, and in admixture with plasticizers, pigments and other substancesto alter the characteristics of the coating. A water-insoluble butwater-permeable diffusion barrier may consist of ethyl cellulose, methylcellulose and mixtures thereof. The water-permeable diffusion barriermay also include ammonio methacrylate copolymers sold under the tradename EUDRAGIT® (Rohm Pharma), such as EUDRAGIT RS, EUDRAGIT RL, EUDRAGITNE and mixtures thereof. Other synthetic polymers, for example,polyvinyl acetate (available under the trade name KOLLICOAT®), can alsobe used to form water-insoluble but permeable coatings.

The coating may also include a water-insoluble but enzymaticallydegradable material. In some instances the substrates of digestiveenzymes are naturally water-insoluble and can be utilized in theformulation without further processing. Solid esters of fatty acids,which are hydrolyzed by lipases, can be spray coated onto microparticlesor drug particles. Mixtures of waxes (beeswax, carnauba wax, etc.) withglyceryl monostearate, stearic acid, palmitic acid, glycerylmonopalmitate and cetyl alcohol will also form films that are dissolvedslowly or broken down in the GI tract. Zein is an example of a naturallywater-insoluble protein. It can be coated onto drug containingmicroparticles or drug particles by spray coating or by wet granulationtechniques. In addition to naturally water-insoluble materials, somesubstrates of digestive enzymes can be treated with cross-linkingprocedures, resulting in the formation of non-soluble networks. Manymethods of cross-linking proteins, initiated by both chemical andphysical means, have been reported. One of the most common methods toobtain cross-linking is the use of chemical cross-linking agents.Examples of chemical cross-linking agents include aldehydes(gluteraldehyde and formaldehyde), epoxy compounds, carbodiimides, andgenipin. In addition to these cross-linking agents, oxidized and nativesugars have been used to cross-link gelatin (Cortesi, R., et al.,Biomaterials 19 (1998) 1641-1649). Cross-linking can also beaccomplished using enzymatic means; for example, transglutaminase hasbeen approved as a GRAS substance for cross-linking seafood products.Finally, cross-linking can be initiated by physical means such asthermal treatment, UV irradiation and gamma irradiation.

To produce a coating layer of cross-linked protein surrounding drugcontaining microparticles or drug particles, a water soluble protein canbe spray coated onto the microparticles and subsequently cross-linked bythe one of the methods described above. Alternatively, drug containingmicroparticles can be microencapsulated within protein bycoacervation-phase separation (for example, by the addition of salts)and subsequently cross-linked. Some suitable proteins for this purposeinclude gelatin, albumin, casein, and gluten.

Polysaccharides can also be cross-linked to form a water-insolublenetwork. For many polysaccharides, this can be accomplished by reactionwith calcium salts or multivalent cations which cross-link the mainpolymer chains. Pectin, alginate, dextran, amylose and guar gum aresubject to cross-linking in the presence of multivalent cations.Complexes between oppositely charged polysaccharides can also be formed;pectin and chitosan, for example, can be complexed via electrostaticinteractions. Insoluble coatings can be formed on particles in thisfashion. It should be noted that in many cases polysaccharides arebroken down specifically by enzymes produced by bacteria within thecolon.

In some cases a water-insoluble but enzymatically degradable coatingincluding both a protein and a polysaccharide can be produced if thecomponents are oppositely charged polyelectrolytes. Under the propertemperature, pH, and concentrations, the two polymers can interactthrough their opposite electrical charges and form a water-insolublecomplex. If a core particle is present at the time the complex phaseseparates, it will be coated. For example, gelatin and gum arabic can becoated onto a core particle utilizing this process. Optionally, thecomplex can be made irreversibly insoluble by subsequent cross-linkinginduced by chemical or physical means.

Coating materials may also include a pH sensitive polymer which isinsoluble in the acid environment of the stomach, and soluble in themore basic environment of the GI tract. Such a coating is thus anenteric coating, creating a dosage form designed to prevent drug releasein the stomach. Preventing drug release in the stomach has the advantageof reducing side effects associated with irritation of the gastricmucosa, and of minimizing exposure of drug to very low pH. Avoidingrelease within the stomach can be achieved using enteric coatings knownin the art. The enteric coated formulation remains intact orsubstantially intact in the stomach, however, once the formulationreaches the small intestines, the enteric coating dissolves and exposeseither drug-containing carrier particles or drug-containing carrierparticles coated with extended release coating.

The enteric coated particles can be prepared as described in“Pharmaceutical dosage form tablets”, eds. Liberman et. al. (New York,Marcel Dekker, Inc., 1989), “Remington—The science and practice ofpharmacy”, 20th ed., Lippincott Williams & Wilkins, Baltimore, Md.,2000, and “Pharmaceutical dosage forms and drug delivery systems”, 6thEdition, Ansel et. al., (Media, Pa. Williams and Wilkins, 1995).Examples of suitable coating materials include, but are not limited to,cellulose polymers, such as cellulose acetate phthalate, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate; polyvinyl acetate phthalate, acrylicacid polymers and copolymers, and certain methacrylic resins that arecommercially available under the trade name EUDRAGIT® (Rohm Pharma).Additionally the coating material may contain conventional carriers suchas plasticizers, pigments, colorants, glidants, stabilization agents,and surfactants.

In some cases it may be desirable to coat the particles with a coatingwhich is soluble in aqueous solutions but insoluble in hydroalcoholicsolutions. In this case the coating material may or may not have pHsensitive solubility in aqueous solutions.

In some cases it may be desirable to combine coating materials toproduce a tailored release of drug. For example, combinations ofinsoluble polymers and pH dependent polymers can produce a pH dependentsustained release profile. Combinations of insoluble polymers (e.g.,ethylcellulose), water-soluble polymers (e.g., HPMC or PEG) and pHdependent swellable polymers (e.g., carboxyvinylpolymer) have also beenreported to produce pH dependent sustained release profiles (See, forexample, Journal of Controlled Release, 2006, 111:309-315)

E. Dosage Forms

There are a number of drug compositions that meet the criteria outlinedabove. In one embodiment a drug is homogeneously dispersed, in a fineparticulate form, within a water-insoluble or slowly water solublematerial and the mixture is formulated into microparticles. In anotherembodiment a drug is partially dissolved within a water-insoluble orslowly water soluble material during the manufacturing process, forexample, by mixing at a temperature above the melting point of thecarrier material, and the mixture is formulated into microparticles. Inyet another embodiment a drug is fully dissolved within awater-insoluble or slowly water soluble material during themanufacturing process, for example, by mixing at a temperature above themelting point of the carrier material, and the mixture is formulatedinto microparticles. In still a further embodiment, the drug containingmicroparticles, where the drug is homogeneously dispersed in aparticulate form, or has been partially or fully dissolved within thecarrier material during the manufacturing process, are coated with oneor more coatings to form coated microparticles.

The microparticles, coated microparticles, or a mixture thereof areformed into a solid dosage form suitable for oral administration. Forexample, microparticles or coated microparticles can be incorporatedinto hard capsules, dispersed within a soft gelatin capsule, or combinedwith appropriate excipients and tableted by compression.

Dosage forms can include one or more drugs. If the drugs are compatible,several different drugs can be incorporated into the same microparticlecomposition or coated microparticle composition. The drugs can beincorporated into separate microparticle compositions where a first drugis formulated into microparticle compositions or coated microparticlecompositions described herein and one or more additional drugs areincorporated into microparticle compostions or coated microparticlecompositions described herein, sustained release compositions known inthe art or immediate release compositions known in the art. Thecompositions including the different drugs are formulated into a singlesolid dosage form suitable for oral administration, for example, theycan be incorporated into a gelatin capsule, or combined with appropriateexcipients and compressed into a tablet form.

An immediate release dose can be incorporated into the formulation inseveral ways. Immediate release microparticles can be made utilizingstandard methodologies and formulated along with sustained releasemicroparticle and/or coated microparticle compositions in a suitableoral dosage form. Alternatively, a coating containing drug which isavailable for immediate release can be placed on a tablet includingsustained release microparticle and/or coated microparticle compositionsplus appropriate excipients. Additionally, an immediate dose of drug canbe granulated or blended with rapidly dissolving excipients andsubsequently compressed (1) as one layer of bi-layer tablets in whichthe sustained release microparticle and/or coated microparticlecompositions are compressed as the other layer, or (2) as the outerlayer of compression-coated tablets in which the sustained releasemicroparticle and/or coated microparticle compositions are compressed asthe inner core, or (3) into tablets in which sustained releasemicroparticle and/or coated microparticle compositions are embedded.

Optional excipients present in the oral dosage form including abusedeterrent microparticles or coated microparticles include, but are notlimited to diluents, binders, lubricants, disintigrants, colorants,plasticizers and the like. Diluents, also termed “fillers,” aretypically necessary to increase the bulk of a solid dosage form so thata practical size is provided for compression of tablets. Examples ofdiluents include cellulose, dry starch, microcrystalline cellulose,dicalcium phosphate, calcium sulfate, sodium chloride confectioner'ssugar, compressible sugar, dextrates, dextrin, dextrose, sucrose,mannitol, powdered cellulose, sorbitol, and lactose. Binders are used toimpart cohesive qualities powdered materials and can include materialssuch as starch, gelatin, sugars, natural and synthetic gums,polyethylene glycol, ethylcellulose, methylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, waxes andpolyvinyl pyrrolidone. Lubricants are used to facilitate tabletmanufacture; examples of lubricants include talc, magnesium stearate,calcium stearate, hydrogenated vegetable oils stearic acid, sodiumstearyl fumarate, sodium benzoate, sodium acetate, leucine, sodiumoleate, sodium lauryl sulfate, magnesium lauryl sulfate and polyethyleneglycol. Disintegrants can be added to pharmaceutical formulations inorder to facilitate “breakup” or disintegration after administration.Materials used for this purpose include starches, clays, celluloses,aligns, gums, and cross-linked polymers. A plasticizer may be includedin coating materials to alter their mechanical properties. Examples ofplasticizers include benzyl benzoate, chlorobutanol, dibutyl sebacate,diethyl phthalate, glycerin, mineral oil, polyethylene glycol, sorbitol,triacetin, triethyl citrate, glycerol, etc. In addition to the additivesabove, coloring and flavoring agents may also be incorporated into thecomposition.

II. Methods of Administration

It is assumed that upon oral ingestion of the intact composition, drugis released as the formulation is gradually broken down or dissolvedwithin the GI tract by a combination of diffusion, surfactant action ofbile acids, mechanical erosion, and, in some embodiments, enzymaticdegradation. This is a result of the unique ability of the humandigestive system to efficiently break down or solubilize a variety ofmaterials. The process within the GI tract that results in the digestionof food and the absorption of nutrients is well known. Followingmastication within the mouth, food passes into the stomach where it ismixed with digestive juices. This fluid contains the proteolytic enzymepepsin which, following activation by the low pH within the stomach,begins the process of cleaving ingested proteins into smaller peptidefragments. Food then enters the small intestine in the form ofmacromolecular aggregates, where it is digested into molecules near orin a form capable of being absorbed. This digestion is accomplishedthrough the action of various enzymes which are produced in the pancreasand flow into the upper portion of the large intestine, the duodenum.The enzymes synthesized in the pancreas include proteases, amylases andlipases; these enzymes are capable of breaking down proteins, starchesand fats, respectively. The digestion of fats is further facilitated bythe secretion of bile into the duodenum since bile salts, which containboth hydrophobic and hydrophilic portions, are capable of emulsifyinglipids into minute droplets in order to increase the surface areaavailable for digestion by lipases. The material which remains followingpassage through the small intestine enters the large intestine. Bacteriacapable of breaking down carbohydrates not digested in the smallintestine (such as cellulose) are present in large numbers this regionof the digestive tract. Finally, in addition to microbial fermentation,the large intestine functions to absorb water and electrolytes and toform and store feces until they are excreted.

In some embodiments, an immediate release of drug is achieved within thestomach in order to provide rapid therapeutic onset.

The pharmaceutical drug composition is administered orally. Theappropriate dosage formulations can be obtained by calculation of thepharmacokinetics of the formulation, then adjusting using routinetechniques to yield the appropriate drug levels based on the approveddosage forms. Any suitable amount of drug containing microparticles orcoated microparticles can be included in the final formulation. Theselection of a suitable amount of drug containing microparticles dependson the dosage desired and is readily determined by those skilled in theart.

In addition to oral administration, some embodiments may also beadministered by other routes, including, but not limited to, rectal andnasal administration. Some embodiments may also be suitable forformulation as oral liquids.

The present composition and method of making and using the compositionwill be further understood by reference to the following non-limitingexamples.

EXAMPLE 1 Preparation of Lipophilic Oxycodone Derivative Oxycodone FreeBase

The free base of oxycodone can be prepared from its hydrochloride saltby the following method: Oxycodone hydrochloride is dissolved in waterand sodium carbonate was added in the amount required to neutralizehydrochloric acid. Methylene chloride is added in order to extract theformed oxycodone free base. The obtained organic layer is dried oversodium sulfate and methylene chloride is evaporated using rotaryevaporator. The obtained oxycodone free base is purified bycrystallization.

EXAMPLE 2 Preparation of Drug Containing Microparticles

TABLE 1 Compositions Composition Composition Composition Composition ofof of of Formulation Formulation Formulation Formulation Ingredient A BC D Oxycodone  5 g  5 g 10 g  5 g Base Myristic Acid — — 50 g 30 gStearic Acid 34 g 34 g — — Yellow 10 g — 10 g 10 g Beeswax Carnauba wax 5 g 10 g 20 g 10 g

Procedure:

1. Fatty acid (myristic or stearic acid) was melted in an erlenmeyerflask in a silicone oil bath at 100° C. Note the composition wassubjected to stirring and was kept under an argon blanket for this andall subsequent steps.2. Oxycodone base was introduced into the molten fatty acid and the meltwas stirred until all oxycodone base dissolved and a clear liquid wasformed.3. Yellow beeswax was added and melted under constant stirring.4. Carnauba wax was added and melted under constant stirring.5. The resulting homogeneous molten solution was poured onto aluminumfoil and allowed to solidify at room temperature.6. The bulk wax obtained was combined with dry ice and subjected to sizereduction in a mortar and pestle.7. The dry ice was allowed to dissipate and the particles were sieved toobtain various size ranges. Particles 20-40 mesh in size (400-841micron) were subjected to testing.

EXAMPLE 3 Release of Drug from Crushed Microparticles

In vitro testing was conducted in order to assess the influence ofcrushing of the microparticles produced in Example 2 on the release insimulated stomach conditions. A currently marketed sustained releaseformulation of oxycodone, OxyContin®, was also subjected to crushing anddissolution for comparison purposes.

Microparticles (Formulations A, B, C or D, all 20-40 mesh in startingparticle size) or tablets were crushed using a glass mortar & pestle.The resulting crushed material was placed in a dissolution vesselequipped with paddles (USP Apparatus II). 900 mL of 0.1N HCl pre-warmedto 37° C. was added to the vessels and stirring was conducted for 15minutes. After 15 minutes the amount of oxycodone released wasdetermined. See Table 2.

TABLE 2 Oxycontin Formulations % Released in 15 minutes in 0.1N HClSample (n = 3) Oxycontin ® 95.6 +/− 2.7 (40 mg Tablet) Formulation A31.6 +/− 2.6 (microparticles containing 40 mg oxycodone HCl equivalent)Formulation B 19.7 +/− 1.4 (microparticles containing 40 mg oxycodoneHCl equivalent) Formulation C 14.8 +/− 1.1 (microparticles containing 20mg oxycodone HCl equivalent) Formulation D 18.2 +/− 1.6 (microparticlescontaining 20 mg oxycodone HCl equivalent)

As illustrated in the table above, the microparticle compositions ofExample 2 release only a fraction of the total drug load in simulatedstomach conditions when crushed. In contrast, a currently marketedsustained release composition, OxyContin®, releases approximately 96% ofthe drug load when crushed and exposed to identical conditions.

EXAMPLE 4 Preparation of Coated Drug Containing Microparticles

The drug-containing particles from Example 2 are spray coated withcellulose acetate phalate.

EXAMPLE 5 Preparation of Capsules for Oral Administration

The drug containing microparticles from Example 2 and/or the coatedmicroparticles from Example 3 are blended with a lubricant andincorporated into standard gelatin capsules.

Modifications and variations of the present invention will be obvious tothose skilled in the art.

1. An orally administrable sustained release pharmaceutical compositioncomprising a therapeutically effective amount of microparticlesconsisting of (a) a lipophilic drug or lipophilic derivative of a drugother than a drug prone to abuse and (b) one or more carrier materialsselected from the group consisting of fats, fatty substances, waxes,wax-like substances and mixtures thereof wherein the drug is dispersedwithin the one or more carrier materials, and the release of a portionof incorporated drug is retarded when the physical integrity of thecomposition is compromised and the compromised composition is exposed to0.1N HCl.
 2. An orally administrable sustained release pharmaceuticalcomposition comprising a therapeutically effective amount ofmicroparticles consisting of a lipophilic derivative of a drug otherthan a drug prone to abuse dispersed within one or more carriermaterials which are either slowly soluble in water or insoluble inwater, wherein the release of a portion of incorporated drug is retardedwhen the physical integrity of the composition is compromised and thecompromised composition is exposed to 0.1N HCl.
 3. The composition ofclaim 1 or 2, wherein the portion of the drug released immediately whenthe physical integrity of the composition is compromised is less than80% of the total amount of drug incorporated into formulation.
 4. Thecomposition of claim 1 or 2, wherein the lipophilic derivative of a drugis a free base or a free acid of the drug.
 5. The composition of claim 1or 2, wherein the lipophilic derivative of a drug is a salt comprisingthe ionized drug and a counter-ion.
 6. The composition of claim 1 or 2,wherein the lipophilic derivative of a drug is an ester or amide formedbetween the drug and a fatty acid.
 7. The composition of claim 5 whereinthe counter-ion is selected from the group consisting of stearic acid,palmitic acid, myristic acid, and mixtures thereof.
 8. The compositionof claim 5 wherein the counter-ion is selected from the group consistingof methacrylic acid-methyl methacrylate copolymers, acrylic acidpolymers, crosslinked acrylic acid polymers and carboxymethylcellulose.9. The composition of claim 2 wherein the microparticles consist of drugdispersed in a material selected from the group consisting of fats,fatty substances, waxes, wax-like substances and mixtures thereof. 10.The composition of claim 1 or 2 comprising one or more carrier materialsselected from the group consisting of stearic acid, palmitic acid, andmixtures thereof.
 11. The composition of claim 1 or 2 comprising one ormore carrier materials selected from the group consisting of beeswax,carnauba wax, hydrogenated oil, and mixtures thereof.
 12. Thecomposition of claim 1 or 2 wherein the carrier materials are selectedfrom the group consisting of myristic acid, palmitic acid, stearic acid,carnauba wax, beeswax and mixtures thereof.
 13. The composition of claim2 wherein the microparticles consist of a drug dispersed in a carriermaterial selected from the group consisting of naturally water insolubleproteins, naturally water insoluble polysaccharides, naturally waterinsoluble lipids and phospholipids, cross-linked water soluble proteins,cross-linked water soluble polysaccharides and combinations thereof. 14.The composition of claim 1 or 2 wherein the individual microparticlesare coated with one or more independent layers.
 15. The composition ofclaim 14 wherein the coated layer(s) comprise a material selected fromthe group consisting of naturally water insoluble proteins, naturallywater insoluble polysaccharides, naturally water insoluble lipids andphospholipids, cross-linked proteins, cross-linked polysaccharides,mixtures of waxes and fatty substances, and combinations thereof. 16.The composition of claim 15 wherein the coated layer(s) comprise amaterial selected from the group of pH dependent coatings, waterinsoluble diffusion barrier coatings, water soluble coatings andcombinations thereof.
 17. The composition of claim 1 or 2 wherein thelipophilic derivative is dissolved in the carrier material in a moltenstate to result in a uniform dispersion within the carrier material. 18.The composition of claim 1 or 2 wherein the lipophilic derivative isdissolved in a co-solvent along with a carrier material to result in auniform dispersion within the carrier material.
 19. The composition ofclaim 1 or 2, wherein the individual microparticles are furtherformulated into a tablet or capsule for oral administration.
 20. Thecomposition of claim 19, wherein the individual microparticles containone or more drugs.
 21. The composition of claim 19, wherein the tabletor capsule further comprises one or more drugs formulated as animmediate release dose, a sustained release dose, a delayed releasedose, or a combination thereof.